Modulation of Immune Activation by Aspirin

HIV-1 Infection Clinical Trial

Official title:

Modulation of Immune Activation by Aspirin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02155985
• Other study ID #: ACTG A5331
• Secondary ID: UM1AI068636
• Status: Completed
• Phase: Phase 2
• First received: June 3, 2014
• Last updated: January 6, 2016
• Start date: August 2014
• Est. completion date: July 2015

Study information

• Verified date: January 2016
• Source: AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Since people started taking HIV medications, illness from AIDS has decreased, but other serious diseases like heart disease, cancer, and kidney, and liver disease have increased. HIV causes inflammation (irritation) inside the body that cannot be felt but can be measured by blood. Inflammation can lead to diseases that have become some of the leading causes of death in people with HIV. HIV therapy can partially lower levels of inflammation measured in blood, however, levels of inflammation in people who have HIV may remain high compared with those found in people not infected with HIV.

Aspirin is a drug that is commonly used for pain relief but is also approved by the Food and Drug Administration (FDA) for preventing heart attacks and stroke in those who are at increased risk for heart attack and stroke. Aspirin also is used (but is not approved by the FDA) to decrease the risk of some cancers in people who are at increased risk. Aspirin is thought to decrease risk of heart attack and stroke because it blocks the activation (turning on) of platelets (small cells in your blood that help it to clot) and prevents blood clots from clogging narrowed blood vessels, a disease called atherosclerosis. It is unknown how aspirin might decrease the chance of developing cancer in some people at higher risk, but aspirin has been shown to modulate (or change) the immune system. In HIV-infected people who have been taking antiretroviral therapy and have an undetectable HIV viral load. It has recently been shown that low-dose aspirin 81 mg (baby aspirin), given for one week, lowers platelet activation and reduces blood markers of inflammation which may improve the function of the immune system. The purpose of the study that you are being asked to participate in is to evaluate whether aspirin improves inflammation and immune activation when compared to a placebo (inactive medication like a dummy pill) and to determine if 12 weeks of aspirin 300 mg and aspirin 100 mg is safe for HIV-infected persons on antiretroviral therapy (ART). Additionally, it will study whether a higher dose and longer duration of aspirin provides further anti-inflammatory (something that prevents irritation) and immune-modulating (something that helps or improves the immune system) benefit. This will be done using blood and urine tests that measure inflammation and also with a test that uses ultrasound to measure the flow of blood in your arm, called flow-mediated vasodilation (FMD) of the brachial artery (BART). This is a painless test that bounces sound waves off of a blood vessel in your arm.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 121
• Est. completion date: July 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• HIV-1 infection.

• Currently on continuous ART for =48 weeks prior to study entry. NOTE: This is defined as continuous active therapy with no treatment interruption longer than 7 consecutive days and a total duration off-treatment of no more than 14 days during the 48 weeks prior to entry.

• No change in ART regimen within the 12 weeks prior to study entry (except as noted below).

NOTE: Modifications of ART dosing during within the 12 weeks prior to entry are permitted. In addition, the change in formulation (eg, from standard formulation to fixed dose combination or single tablet regimen) or dosing (eg, from once a day to twice a day) is allowed within 12 weeks prior to entry. Within-class single drug substitution (eg, switch from nevirapine to efavirenz or from atazanavir to darunavir), are not allowed within 12 weeks prior to entry. No other changes in ART in the 12 weeks prior to entry are permitted.

• Screening HIV-1 RNA must be <50 copies/mL and performed by any FDA-approved assay at any US laboratory that has a CLIA certification or its equivalent within 45 days prior to study entry.

• Maintain ART-mediated viral suppression for at least 48 weeks prior to study entry defined as:

A. At least one HIV-1 RNA test result obtained at any time point greater than 48 weeks prior to study entry must be BLQ and must be performed by any FDA-approved assay at a CLIA-certified laboratory or its equivalent.

AND

B. All HIV-1 RNA tests reported during the 48 weeks prior to study entry must be BLQ and must be performed by any FDA-approved assay at a CLIA-certified laboratory or its equivalent.

NOTE: A single RNA "blip" of =500 copies/mL is permissible if RNA levels most recent before and after (may include the screening HIV-1 RNA test) are below the level of quantification (BLQ) for the assay. If the RNA level after the blip is the screening HIV-1 RNA test, the result must be <50 copies/mL.

• The following laboratory values obtained within 45 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent.

• Absolute neutrophil count (ANC) =750/mm3

• Hemoglobin =9.0 g/dL for female subjects and =10.0 g/dL for male subjects

• Platelet count >100,000/mm3

• Prothrombin time (PT) <1.2 x upper limit normal (ULN)

• Partial thromboplastin time (PTT) <1.5 x ULN

• Calculated creatinine clearance (CrCl) =30 mL/min, as estimated by the Cockroft-Gault formula NOTE: Calculation for the Cockcroft-Gault equation is available at https://www.fstrf.org/apps/cfmx/apps/common/Portal/index.cfm

• Aspartate aminotransferase (AST) (SGOT) =2 x ULN.

• Alanine aminotransferase (ALT) (SGPT) =2 x ULN.

• Alkaline phosphatase =2 x ULN.

• Total bilirubin =2.5 x ULN. If the subject if taking an indinavir- or atazanavir-containing regimen at the time of screening, a total bilirubin of =5 x ULN is acceptable.

• Female study volunteers of reproductive potential (pre-menopausal women who have not had a sterilization procedure (eg, hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy) must have a negative serum or urine pregnancy test performed within 24 hours prior to study entry. Women are considered menopausal if they have not had a menses for at least 12 months and have a FSH (follicle stimulating hormone) of greater than 40 IU/L or, if FSH testing is not available, they have had amenorrhea for 24 consecutive months.

If the female volunteer is not of reproductive potential (women who are menopausal, defined as not having had a menses for at least 12 months with an FSH of greater than 40 IU/L, or if FSH testing is not available, have had amenorrhea for 24 consecutive months, or women who have undergone surgical sterilization, (eg, hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy)), she is eligible without requiring the use of a contraceptive method. Acceptable documentation of sterilization is subject reported history of hysterectomy, bilateral oophorectomy, tubal ligation, tubal micro-insert, menopause, or the partner with vasectomy/azoospermia.

• If participating in sexual activity that could lead to pregnancy, the female study volunteer must be willing to use contraception while receiving protocol-specified medication(s) and for the washout period of 4 weeks. At least one of the following methods MUST be used:

• Condoms (male or female), with or without a spermicidal agent

• Diaphragm or cervical cap with spermicide

• Intrauterine device (IUD)

• Hormone-based contraceptive

As hormone-based contraceptives (oral, transdermal, or subdermal) can affect coagulopathy biomarkers, subjects who plan on using such a contraceptive during the study must be taking the same product for =4 weeks prior to screening and be encouraged to continue throughout the duration of the study, if medically feasible.

• No documented opportunistic infections within 24 weeks prior to study entry

• Karnofsky performance score >/= 70 within 45 days prior to study entry

• Ability and willingness of subject or legal guardian/representative to provide written informed consent.

• Willingness to refrain from the use of aspirin or any aspirin-related product (other than the study drug), including NSAIDs, from time of screening visit through the end of the 16 week trial.

NOTE: Acetaminophen-based products may be used before and during the trial when analgesics are required.

• Completion of the pre-entry FMD assessment NOTE: The FMD must be performed at the site and confirmed as acceptable by the University of Wisconsin Atherosclerosis Imaging Research Program (UW AIRP) core lab prior to study entry.

• Confirmation of the availability of the stored pre-entry fasting specimens (plasma and serum); the site must confirm that these specimens have been entered into the Laboratory Data Management System (LDMS).

Exclusion Criteria:

• Current malignancy (except non-melanoma cancer of the skin not requiring systemic chemotherapy or radiation therapy).

NOTE: Carcinoma in situ of the cervix or anus is not considered exclusionary.

• Prior history of malignancy if the subject is not disease free for 24 or more weeks prior to study entry.

• Current use or indication for use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin that cannot be interrupted for clinical reasons. Examples of clinical reasons include, but are not limited to, known and documented cardiovascular disease (history of MI, coronary artery bypass graft surgery, percutaneous coronary intervention, stroke, transient ischemic attack, peripheral arterial disease with ABI <0.9 or claudication).

• Current diagnosis of diabetes with HbA1c =8% within 24 weeks prior to screening.

• Changes in lipid-lowering or antihypertensive medication within 90 days prior to study entry or expected need to modify these medications during the study.

NOTE: Lipid-lowering medication includes: statins, fibrates, niacin (dose =250 mg daily), and fish-oil/omega 3 fatty acids (dose >1000 mg of marine oils daily).

• Known cirrhosis

• Known chronic active hepatitis B NOTE: Active hepatitis B is defined as hepatitis B surface antigen positive and hepatitis B DNA positive within 24 weeks prior to study entry; subjects with hepatitis B virus (HBV) DNA BLQ for greater than 24 weeks prior to study entry are eligible.

• Known chronic active hepatitis C NOTE: Active hepatitis C is defined as a detectable plasma HCV RNA level within 24 weeks prior to study entry; subjects with HCV RNA BLQ for greater than 24 weeks prior to study entry are eligible.

• Known inflammatory conditions, such as, but not limited to, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sarcoidosis, inflammatory bowel disease (IBD), chronic pancreatitis, autoimmune hepatitis, Adult Stills disease, Rheumatic heart disease, bursitis.

• Breastfeeding or pregnant

• Previous intolerance or allergy to aspirin or any aspirin products.

• Frequent use of aspirin or aspirin products (NSAIDs), defined as an average of 2 or more times per week in the last 12 weeks prior to study entry.

• Immunosuppressant use, such as, but not limited to, systemic or potentially systemic glucocorticoids (including injected, ie, intra-articular, nasal or inhaled steroids), azathioprine, tacrolimus, mycophenolate, sirolimus, rapamycin, methotrexate, or cyclosporine within 45 days prior to study entry.

• Use of any systemic antineoplastic or immunomodulatory treatment, investigational vaccines, interleukins, interferons, growth factors, or intravenous immunoglobulin (IVIG) within 45 days prior to study entry.

NOTE: Routine standard of care, including hepatitis A and/or B, human papilloma virus, influenza, pneumococcal, and tetanus vaccines are permitted if administered at least 7 days before study entry and before biomarker/peripheral blood mononuclear cell (PBMC) blood collections.

• Concurrent use of prohibited medications as per section 5.4

• Heavy alcohol use as defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking

• Alcohol or drug use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.

• Current use of anticoagulation therapy or conditions requiring use of anticoagulants, use such as, but not limited to warfarin (Coumadin), rivaroxaban (Xarelto), clopidogrel (Plavix), dabigatran (Pradaxa), apixaban (Eliquis), heparin, ticlopidine (Ticlid), Presugrel (Effient).

• History of coagulopathy, deep venous thrombosis, pulmonary embolism.

• Known active or recent (not fully resolved within 4 weeks prior to study entry) invasive bacterial, fungal, parasitic, or viral infections.

NOTE: Recurrent herpes simplex virus (HSV) is not exclusionary. Subjects on antiviral prophylaxis for HSV or VZV are encouraged to remain on treatment for the duration of the study if medically feasible.

• Serious illness or trauma requiring systemic treatment and/or hospitalization within 4 weeks prior to study entry.

• History of bleeding conditions such as peptic ulcer disease, hemophilia, von Willebrand disease, idiopathic thrombocytopenic purpura.

• History of thrombotic disorders such as protein C or S deficiency.

• History of gastrointestinal (GI) bleeding within the past 6 months prior to study entry.

• History of intracranial hemorrhage.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• Aspirin

• Aspirin placebo

Locations

Country	Name	City	State
United States	University of Colorado Hospital CRS (6101)	Aurora	Colorado
United States	Brigham and Women's Hosp. ACTG CRS (107)	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS (101)	Boston	Massachusetts
United States	3201 Chapel Hill CRS	Chapel Hill	North Carolina
United States	2701 Northwestern University CRS	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS (2702)	Chicago	Illinois
United States	Univ. of Cincinnati CRS (2401)	Cincinnati	Ohio
United States	Case CRS (2501)	Cleveland	Ohio
United States	Greensboro CRS (3203)	Greensboro	North Carolina
United States	Houston AIDS Research Team CRS (31473)	Houston	Texas
United States	601 University of California, Los Angeles CARE Center CRS	Los Angeles	California
United States	3652 Vanderbilt Therapeutics (VT) CRS	Nashville	Tennessee
United States	701 University of California, San Diego AntiViral Research Center CRS	San Diego	California
United States	Ucsf Aids Crs (801)	San Francisco	California
United States	Harbor-UCLA Med. Ctr. CRS (603)	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
AIDS Clinical Trials Group	National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in sCD14 from baseline to week 12		12 weeks	No
Secondary	Safety and Tolerability	Summary of the number of subjects with at least one grade 3 or higher sign/symptom or laboratory abnormality	16 weeks	Yes
Secondary	Change in sCD163 from baseline to week 12		12 weeks	No
Secondary	Change in CD14 from baseline to week 12		12 weeks	No
Secondary	Change in CD16 from baseline to week 12		12 weeks	No
Secondary	Change in CD69 from baseline to week 12		12 weeks	No
Secondary	Change in CD4+CD38+ cell proportion from baseline to week 12		12 weeks	No
Secondary	Change in CD4+HLA-DR+ cell proportion from baseline to week 12		12 weeks	No
Secondary	Change in CD8+CD38+ cell proportion from baseline to week 12		12 weeks	No
Secondary	Change in CD8+HLA-DR+ cell proportion from baseline to week 12		12 weeks	No
Secondary	Change in expression of PD-1 on CD4+ from baseline to week 12		12 weeks	No
Secondary	Change in expression of PD-1 on CD8+ from baseline to week 12		12 weeks	No
Secondary	Change in expression of CTLA-4 on CD4+ from baseline to week 12		12 weeks	No
Secondary	Change in expression of CTLA-4 on CD8+ from baseline to week 12		12 weeks	No
Secondary	Change in IL-6 from baseline to week 12		12 weeks	No
Secondary	Change in d-dimer from baseline to week 12		12 weeks	No
Secondary	Change in kynurenine to tryptophan ratio from baseline to week 12		12 weeks	No
Secondary	Change in serum thromboxane B2 from baseline to week 12		12 weeks	No
Secondary	Change in 11-dehydrothromboxane B2 from baseline to week 12		12 weeks	No
Secondary	Change in brachial artery FMD from baseline to week 12		12 weeks	No